The current obesity epidemic in the US is the major contributor to the soaring rates of metabolic diseases and to skyrocketing health care costs. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood, and therapeutic interventions for obesity and related metabolic abnormalities are limited. In recent years, thousands of long non-coding RNAs lncRNAs (lncRNAs) have been identified to constitute a significant portion of mammalian genomes. Interestingly, half of SNPs associated with diseases including metabolic disease fall in the noncoding regions suggesting that dysfunction of lncRNAs might be pathogenic. However, the pathophysiological roles of most lncRNAs remain poorly understood and their implications in metabolic disorder are largely unexplored. We have recently demonstarted that a liver-enriched lncRNA robustly reuglates systemic lipid metaoblism in vivo (Li et al, Cell Metabolism, 2015) and a second lncRNA regulates critical aspects of glucose metabolism in mice (Ruan et al, Cell Reports, 2016). To systemically identify functional lncRNAs regulating energy metabolism, we performed over 100 transcriptome analyses to simultaneously profile mRNAs and lncRNAs in key metabolic organs in mice under pathophysiologically representative metabolic conditions. Similar to mRNAs, the lncRNA transcriptome in each tissue forms a metabolic signature reflecting the animals metabolic or disease condition. Out of 4759 regulated lncRNAs, function-orientated filters yield 359 tissue-specifically regulated and metabolically sensitive lncRNAs which are predicted by lncRNA-mRNA correlation analyses to function in diverse aspects of energy metabolism. Specific regulations of liver metabolically sensitive lncRNAs (lncLMS) by individual nutrients, metabolic hormones and key transcription factors were further defined in primary hepatocytes, connecting these lncRNAs to metabolic signaling pathways. Combining the extensive genome-wide screens, bioinformatics function predictions and cell-based analyses, we have developed an integrative roadmap to identify functional lncRNA metabolic regulators in vivo. An lncLMS, predicted to regulate lipid metabolism by our roadmap, was experimentally confirmed in mice to suppress lipogenic gene expression and circulating triglyceride levels by forming a negative feedback loop in the SREBP1c pathway. Taken together, our data support that a class of lncRNAs function as important metabolic regulators, and this study establishes a framework for systemically investigating the role of lncRNAs in physiological homeostasis and the potential to adapt these molecules for novel therapies (Yang et al, in press in Cell Metabolism, 2016).